COL3A1haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy

Leistritz, Dru F.; Pepin, Melanie G.; Schwarze, Ulrike; Byers, Peter H.

doi:10.1097/gim.0b013e3182180c89

Cited by 141Connective tissue disorders researchDermatological and Skeletal DisordersGenomics and Rare Diseases

COL3A1haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy

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Leistritz, Dru F., Pepin, Melanie G., Schwarze, Ulrike, Byers, Peter H.·2011·Genetics in Medicine

DOI 10.1097/gim.0b013e3182180c89

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Abstract

Purpose To characterize the clinical outcome of heterozygosity for COL3A1 null mutations in Ehlers-Danlos syndrome type IV, the vascular type.Methods We identified mutations that produced premature termination codons and resulted in nonsense-mediated messenger RNA decay in 19 families. We reviewed the clinical and family histories and medical complications in 54 individuals from these families with COL3A1 null mutations.Results Compared with individuals with missense or exon-skipping mutations, we found that life span was extended, the age of first complication was delayed by almost 15 years, and major complications were limited to vascular events. The families were ascertained after a complication in a single individual, but only 28% of relatives, some of whom had reached their seventies or eighties without incidents, had a complication and only 30% had minor clinical features of Ehlers-Danlos syndrome type IV CONCLUSION: Null mutations have reduced penetrance compared with missense and splicing mutations, and the phenotype seems to be limited almost entirely to vascular events.

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Splice site mutations that lead to exon skipping have the lowest median survival.
“Splice site mutations that lead to exon skipping have the lowest median survival.”
From Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome (2018) · cites this paper as [12]
The nature of the specific COL3A1 mutation influences life expectancy.
“the nature of the specific COL3A1 mutation influences life expectancy.”
From Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome (2018) · cites this paper as [12]
Mutations leading to premature termination of translation and nonsense-mediated mRNA decay are rare (less than 5%).
“Mutations leading to premature termination of translation and nonsense-mediated mRNA decay are rare (less than 5%).”
From Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome (2018) · cites this paper as [12]
Substitutions of bulky residues (Arg, Asp, Glu, Val) for glycine residues in the triple helical domain are usually less severe than splice site mutations, but more consequential than substitutions by smaller residues (Ala, Ser, Cys).
“Substitutions of bulky residues (Arg, Asp, Glu, Val) for glycine residues in the triple helical domain are usually less severe than splice site mutations, but more consequential than substitutions by smaller residues (Ala, Ser, Cys).”
From Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome (2018) · cites this paper as [12]
Heterozygosity for COL3A1 null alleles typically produces a milder clinical phenotype with a significant delayed onset of complications.
“Heterozygosity for COL3A1 null alleles typically produces a milder clinical phenotype with a significant delayed onset of complications [4, 9–12].”
From Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome (2018) · cites this paper as [12]

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Survival is affected by mutation type and molecular mechanism in vascular Ehlers–Danlos syndrome (EDS type IV)
Pepin, M. G., Schwarze, U., Rice, K. M., Liu, M., Leistritz, & Byers, P. H. (2014) · Genetics in Medicine · doi:10.1038/gim.2014.72 · Cited by 313 · see citing works
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Homozygosity for a null allele of COL3A1 results in recessive Ehlers–Danlos syndrome
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Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV
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Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type
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Paternally derived de novo interstitial duplication of proximal 15q in a patient with developmental delay
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Authors: Leistritz, D. F., Pepin, M. G., Schwarze, U., & Byers, P. H.
Affiliations: University of Washington (US)
Corresponding author: Byers, Peter H.
ORCID: Byers, Peter H.
Venue: Genetics in Medicine
Publisher: Elsevier BV
Published: 2011-08
Volume: 13
Issue: 8
Pages: 717-722
ISSN: 1098-3600 (ISSN-L)
DOI: 10.1097/gim.0b013e3182180c89
OpenAlex: W2076783554
Cited by: 141
References: 10
Citations by year: 2026: 13 · 2025: 12 · 2024: 8 · 2023: 4 · 2022: 13 · 2021: 8 · 2020: 7 · 2019: 13 · 2018: 8 · 2017: 7 · 2016: 9 · 2015: 9 · 2014: 15 · 2013: 6 · 2012: 6
FWCI: 5.97
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 3824 d)
Locations: Genetics in Medicine (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords: Ehlers-Danlos syndrome type IV, COL3A1, haploinsufficiency, null mutations, premature stop codon, nonsense-mediated mRNA decay, penetrance, life expectancy, vascular complications, family history (medicine)
MeSH terms: Adolescent, Adult, Aged, Aged, 80 and over, Aneurysm, Child, Child, Preschool, Ehlers-Danlos Syndrome, Female, Humans, Life Expectancy, Male, Middle Aged, Mutation, Sequence Analysis, DNA, Penetrance, Collagen Type III, Kaplan-Meier Estimate, Young Adult, Genetic Association Studies, Haploinsufficiency

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COL3A1haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy

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